Cancer remains a pressing medical and public health problem, in spite of decades of research into the molecular and genetic mechanisms underlying the development of this disease. It is well established that human cancers develop in a multistep sequence with environmental influences including chemical, physical, and viral agents being major etiological contributors. Numerous transitions occur in a “tumorigenic progression” as cells change from “normal” to “immortalized” to “transformed” and finally to the “metastatic state.” These changes that produce tumors all occur in a variety of in vivo microenvironments. Recent studies indicate that cancer cells release exosomes that migrate ahead and attach at distant locations and somehow prepare these microenvironments for the progressing tumorigenic cells to settle into as they arrive to establish a metastatic tumor. The classical textbook view of a gradual accumulation of genomic alterations in this progression has been enlightened using next generation whole genome sequencing (WGS) and spectral karyotyping (SKY) with the recent description of stochastic cancer genome fragment rearrangements.
Current studies of transformation and tumor progression often rely on the use of primary embryonic cells or cell lines as a model to evaluate the myriad effects of various treatments on cells progressing from normal to pre-malignant to malignant and even metastatic potential. However, model systems that provide for the ability to evaluate the anti-neoplastic potential of candidate therapeutic agents against a series of increasingly aggressive tumors which are derived sequentially from a single progenitor cell type are needed. As the progressively aggressive tumors produced by this model would be derived from the same progenitor cell type in vivo in a variety of actual non-human animal microenvironments, such a model would more closely recapitulate the normal transitions observed in human cancers as they progress in vivo from localized tumors into a more virulent metastatic state. The ability to preserve and use these cells from these tumors for further characterization and studies of anti-neoplastic agents illustrates the uniqueness of this series of cells that have been generated by this novel serially extended in vivo/in vitro approach.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.